Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Biochem Biophys Res Commun. 2012 Jun 29;423(2):229-33. doi: 10.1016/j.bbrc.2012.05.060. Epub 2012 May 31.
Intercellular spaces between adjacent mucosal epithelial cells are sealed by tight junctions (TJs) that prevent the free movement of solutes across the epithelium. Claudins (CLs), a family of 27 integral membrane proteins, are essential components for TJ seals. We previously used a CL-3/-4 binder, the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), to show that CL modulation is a promising method to enhance mucosal absorption. Recently, by using a C-CPE mutant library, we developed a CL binder (m19) with broad specificity to CL-1, -2, -4, and -5. Here, we compared the mucosal absorption-enhancing activity of C-CPE and m19. Both CL binders enhanced jejunal absorption of dextran with a molecular mass of 4000 and 150,000 Da and nasal absorption of dextran with a mass of 4000 Da but not 150,000 Da in rats. Although both binders showed similar nasal absorption-enhancing activity of dextran (4000 Da), m19 exhibited a more potent jejunal absorption-enhancing effect than that of C-CPE. These findings suggest that mucosal absorption-enhancing activity may be modified by modulating CL specificity.
相邻黏膜上皮细胞之间的细胞间隙由紧密连接 (TJ) 封闭，TJ 阻止溶质自由穿过上皮细胞。紧密连接蛋白 (CLs) 是一类 27 种完整膜蛋白，是 TJ 封闭的必需组成部分。我们之前使用 CL-3/-4 结合物，即产气荚膜梭菌肠毒素的 C 端片段 (C-CPE)，表明 CL 调节是增强黏膜吸收的一种有前途的方法。最近，我们通过使用 C-CPE 突变文库，开发了一种具有广泛特异性的 CL 结合物 (m19)，可与 CL-1、-2、-4 和 -5 结合。在这里，我们比较了 C-CPE 和 m19 的增强黏膜吸收活性。两种 CL 结合物均增强了 4000 和 150000 Da 相对分子质量的葡聚糖在大鼠空肠中的吸收和 4000 Da 葡聚糖的鼻内吸收，但不增强 150000 Da 葡聚糖的鼻内吸收。尽管两种结合物对 4000 Da 葡聚糖的鼻内吸收增强活性相似，但 m19 对空肠吸收的增强作用比 C-CPE 更强。这些发现表明，通过调节 CL 的特异性可以改变黏膜吸收增强活性。
